title: Activation of the activin A-ALK-Smad pathway in systemic sclerosis.
abstract: Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-β) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-β superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1α mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Takagi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ota
authors.forename: Akiko
authors.initials: A
authors.lastname: Tochimoto
authors.forename: Takahisa
authors.initials: T
authors.lastname: Gono
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Masako
authors.initials: M
authors.lastname: Hara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000502:physiology*; D028341:Activins / Q000502:physiology*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D009569:Nitric Oxide; D003094:Collagen; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I